17-Beta-keto-3-oxo-4-aza-5-.alpha.-androst-1-ene steroids are known in the art as benign prostatic hypertrophy (BPH) agents. See European Publication No. 0 155 096 and U.S. Pat. Nos. 4,220,775 and 4,377,584, all assigned to Merck & Co., Inc. Synthetic routes for their preparation are also described in Synthesis, November 1980, pp. 878-890 and Helv. Chim. Acta, Vol. 69 (1986), pp. 228-235.
General routes for synthesis of 17-beta keto androstenones normally involve a Grignard reaction. For example, the 17-beta thiopyridyl ester (see reference J. Med. Chem., Vol. 29, No. 11, pp. 2298-2315 by Rasmusson, et al.) or the 17-beta imidazolide (see reference J. Med. Chem., Vol. 29, No. 11, pp. 2298-2315 by Rasmusson, et al.) can be reacted with suitable Grignard reagent to produce the 17-beta keto derivatives.
However, in general, these intermediates are very reactive, require special handling, and produce intermediates products which are difficult to purify.
Because of convenience and lower process costs, a common route used to make these materials is via a Grignard reaction in which an androstenone 17-beta carboxylic alkyl ester, e.g. methyl ester, which is more stable than the corresponding thiopyridyl ester or imidazolide, is reacted with a Grignard reagent, e.g. isobutylmagnesium bromide. However, the yields are modest, e.g. 30-60%, due to the fact that the desired product ketone reacts further with the Grignard reagent as it is formed to produce the undesired secondary and tertiary alcohols. This situation generally necessitates chromatographic separation of impurities formed in the process, e.g. the secondary and tertiary alcohols, which is not commercially practical on a large scale.
What is desired in the art is a more convenient, higher yielding process which does not involve time-consuming and costly purification procedures.